Transforming Growth Factor TGF Research Articles

Study of Some Hormonal and Biochemical Parameters among Patients with Chronic Liver Diseases

It has been revealed previously that chronic liver disease (CLD) may be associated to hormonal fluctuations. The current study, therefore, aimed to evaluate some hormones in CLD patients compared with non-CLD individuals. This case control study was conducted at Gastroenterology and Hepatology Teaching Hospital, Medical city, Baghdad, Iraq during December 2021 to May 2022. One hundred and twenty male patients with CLD (age:14-75 years) and 120 control males (age: 24-70 years) were involved in this study. Serum samples were taken from all individuals and were then analysed for many tests which included hormones (Cortisol, testosterone, prolactin, insulin and thyroid stimulating hormone TSH); biochemical analysis (Prothrombin time PT, international normalized ratio INR and albumin); liver enzymes (aspartate aminotransferase AST, alanine aminotransferase ALT, alkaline phosphatase ALP and gamma glutamyl transferase (GGT)) and interleukins (Interleukin 13 IL-13 and transforming growth factor TGF). Some hormones such as cortisol, prolactin and insulin significantly increased in CLD patients while other hormones (testosterone and TSH) significantly decreased in CLD patients compared with the controls. Results also showed significant increase in liver enzymes among CLD patients. These changes in the hormones and liver enzymes levels may be related with significant increase in INR and albumin which were significantly higher in CLD patients than in the control group. Finally, IL-13 increased significantly in CLD patients while no significant differences were noticed between CLD and control regarding TGF levels. It can, therefore, be concluded that hormonal imbalance can affect people with liver conditions. and that this hormonal imbalance may be associated with high levels of liver enzymes.

Dietary methionine source alters the lipidome in the small intestinal epithelium of pigs

Methionine (Met) as an essential amino acid has key importance in a variety of metabolic pathways. This study investigated the influence of three dietary Met supplements (0.21% L-Met, 0.21% DL-Met and 0.31% DL-2-hydroxy-4-(methylthio)butanoic acid (DL-HMTBA)) on the metabolome and inflammatory status in the small intestine of pigs. Epithelia from duodenum, proximal jejunum, middle jejunum and ileum were subjected to metabolomics analysis and qRT-PCR of caspase 1, NLR family pyrin domain containing 3 (NLRP3), interleukins IL1β, IL8, IL18, and transforming growth factor TGFβ. Principal component analysis of the intraepithelial metabolome revealed strong clustering of samples by intestinal segment but not by dietary treatment. However, pathway enrichment analysis revealed that after L-Met supplementation polyunsaturated fatty acids (PUFA) and tocopherol metabolites were lower across small intestinal segments, whereas monohydroxy fatty acids were increased in distal small intestine. Pigs supplemented with DL-HMTBA showed a pronounced shift of secondary bile acids (BA) and sphingosine metabolites from middle jejunum to ileum. In the amino acid super pathway, only histidine metabolism tended to be altered in DL-Met-supplemented pigs. Diet did not affect the expression of inflammation-related genes. These findings suggest that dietary supplementation of young pigs with different Met sources selectively alters lipid metabolism without consequences for inflammatory status.

Abstract 1793: Gastrin-releasing peptide causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells

Abstract Gastrin releasing peptide (GRP) is a 27 amino acid peptide which is present in many lung cancer cell lines (Moody et al., Science 1981; 214: 1246). High expression of the GRP receptor (R) is associated with advanced non-small cell lung cancer (NSCLC) (Mattei et al., Arch Pathol Lab Med 2014; 138: 98). GRP stimulates but the GRPR antagonist PD176252 inhibits the proliferation of NSCLC cells (Moody et al., Eur J Pharmacol 2003; 474: 21). Here the effects of GRP on the transactivation of the EGFR and HER2 were investigated in NSCLC cells. Six of 8 NSCLC tested had GRP-R mRNA whereas all the NSCLC cells had EGFR and HER2 mRNA. Addition of GRP to NCI-H1299 cells elevated cytosolic Ca2+, increased tyrosine phosphorylation of the ERK, EGFR and HER2 and increased colony number. The effects of GRP were blocked by PD176252. The transactivation of the EGFR and HER2 was inhibited by gefitinib (EGFR tyrosine kinase inhibitor (TKI)), lapatinib (EGFR and HER2 TKI), GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti-oxidant) and transforming growth factor TGF) α antibody. By ELISA, GRP increased secretion of TGFα from lung cancer cells. PD176252, gefitinib, lapatinib and trastuzumab inhibited NSCLC growth. Activation of the GRPR in NSCLC cells may facilitate the formation of EGFR homodimers and EGFR/HER2 heterodimers. Citation Format: Terry W. Moody, Irene Ramos Alvarez, Robert T. Jensen. Gastrin-releasing peptide causes transactivation of the EGFR and HER2 in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1793.

TGF beta in the rheumatoid arthritis research

Rheumatoid arthritis (RA) is a chronic inflammatory disease of joints primarily, which is characterized by immune cell infiltration and hyperplastic growth of resident cells and blood vessles in synovial tissues. Despite that biomarker research in RA has progressed greatly, the pathogenesis is still not well defined. Transforming growth factor TGF beta is a homodimeric cytokine with multiple functions in embryonic development, immune responses, inflammation and repair. The involvement of TGF beta in RA has been under investigation for a long period in various contexts. The structure and activation of TGFB1, TGFB2 and TGFB3 have been reviewed and compared in this review. Its profibrotic and immunosuppressive function has been discussed in multiple diseases especially in terms of RA pathogenesis.

Abstract 1306: SR48692 inhibits EGF receptor transactivation and proliferation of lung cancer cells.

Abstract Neurotensin (NTS) is an autocrine growth factor for some lung cancer cells (Moody et al., 1985;Life Sci 36:1727). NTS binds with high affinity to the GPCR NTSR1 causing phosphatidyl inositol turnover and proliferation of lung cancer cells; SR48692 is a NTSR1 antagonist (Moody et al., 2001; Peptides 22:109). NTSR1 expression is associated with poor survival of non-small cell lung cancer (NSCLC) patients (Alfano et al., 2010; Clin Cancer Res 16:4401). NSCLC cells express the epidermal growth factor receptor (EGFR) whose tyrosine kinase activity is inhibited by gefitinib. Here the abillity of SR48692 to block EGFR transactivation caused by NTS was investigated. NTS and NTS8-13 but not NTS1-8 addition to NSCLC cell lines NCI-H1299 or A549 cells increased phosphorylation of Tyr1068 of the EGFR after 2 min which was blocked by 10 uM SR48692 or 10 ug/ml gefitinib. The ability of NTS to regulate EGF receptor transactivation was blocked by GM6001 (matrix metalloprotease inhibitor), PP2 (Src inhibitor), N-acetylcysteine (anti-oxidant) and transforming growth factor TGF) α antibody. By ELISA, NTS significantly increased secretion of TGFα from lung cancer cells. NTS but not levocabastine (NTSR2 agonist) increased cytosolic Ca2+ within seconds after addition to NCI-H1299 cells which was antagonized by SR48692. NTS addition to NCI-H1299 cells increased tyrosine phosphorylation of beta-catenin, ERK, FAK, PYK-2 and Src which was antagonized by SR48692. SR48692 inhibited the proliferation of NCI-H1299 and A549 cells which have wild type EGFR. Also, SR48692 potentiated the ability of gefitinib to inhibit growth of NCI-H1299 and A549 cells. These results indicate that SR48692 is a NTSR1 antagonist which increases the potency of gefitinib in lung cancer cells. Citation Format: Terry W. Moody, Robert T. Jensen. SR48692 inhibits EGF receptor transactivation and proliferation of lung cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1306. doi:10.1158/1538-7445.AM2013-1306

Role of Vitamin D in the Immune System

Vitamin D is suggested to be an important immune system regulator. 1,25 dihydroxyvitamin D (1,25(OH)2D3), which is the active form of vitamin D, decreases the proliferation of purifi ed T-helper (Th)1 cells as well as the production of interferon (IFN) γ, interleukin (IL)-2, IL-5 and tumor necrosis factor-alpha (TNF-)α. In Th2 cells, 1,25 (OH)2D3 stimulates IL-4 and transforming growth factor TGF production, which in turn may suppress infl ammatory T cell activity. In the absence of vitamin D signaling, the T cell compartment has a potentially stronger Th1 phenotype. Furthermore, 1,25(OH)2D3 inhibits dendritic cell (DC) differentiation and maturation, leading to down-regulated expression of major histocompatibility complex class II molecules (MHC-II), co-stimulatory molecules and IL-12; enhances IL-10 production and promotes DC apoptosis. Because of these effects, 1,25(OH)2D3 inhibits DC-dependent T cell activation. In vitro, it is determined that 1,25(OH)2D3 stimulates phagocytosis and killing of bacteria by macrophages, but suppresses the antigen presenting capacity of these cells and dendritic cells. Additionally, Chen et al. have suggested that vitamin D might have a role in regulating antibody production. They have found that 1,25(OH)2D3 not only inhibits activated B cell proliferation but induces their apoptosis as well. Turk Jem 2013; 17: 5-7

Clinical use of probiotics in pediatrics.

Clinical use of probiotics in pediatrics.

Tissue-specific Mechanisms for CCN2/CTGF Persistence in Fibrotic Gingiva

Prostaglandin E(2) blocks transforming growth factor TGF beta1-induced CCN2/CTGF expression in lung and kidney fibroblasts. PGE(2) levels are high in gingival tissues yet CCN2/CTGF expression is elevated in fibrotic gingival overgrowth. Gingival fibroblast expression of CCN2/CTGF in the presence of PGE(2) led us to compare the regulation of CCN2/CTGF expression in fibroblasts cultured from different tissues. Data demonstrate that the TGFbeta1-induced expression of CCN2/CTGF in human lung and renal mesangial cells is inhibited by 10 nm PGE(2), whereas human gingival fibroblasts are resistant. Ten nm PGE(2) increases cAMP accumulation in lung but not gingival fibroblasts, which require 1 mum PGE(2) to elevate cAMP. Micromolar PGE(2) only slightly reduces the TGFbeta1-stimulated CCN2/CTGF levels in gingival cells. EP2 prostaglandin receptor activation with butaprost blocks the TGFbeta1-stimulated expression of CCN2/CTGF expression in lung, but not gingival, fibroblasts. In lung fibroblasts, inhibition of the TGFbeta1-stimulated CCN2/CTGF by PGE(2), butaprost, or forskolin is due to p38, ERK, and JNK MAP kinase inhibition that is cAMP-dependent. Inhibition of any two MAPKs completely blocks CCN2/CTGF expression stimulated by TGFbeta1. These data mimic the inhibitory effects of 10 nm PGE(2) and forskolin that were dependent on PKA activity. In gingival fibroblasts, the sole MAPK mediating the TGFbeta1-stimulated CCN2/CTGF expression is JNK. Whereas forskolin reduces TGFbeta1-stimulated expression of CCN2/CTGF by 35% and JNK activation in gingival fibroblasts, micromolar PGE(2)-stimulated JNK in gingival fibroblasts and opposes the inhibitory effects of cAMP on CCN2/CTGF expression. Stimulation of the EP3 receptor with sulprostone results in a robust increase in JNK activation in these cells. Taken together, data identify two mechanisms by which TGFbeta1-stimulated CCN2/CTGF levels in human gingival fibroblasts resist down-regulation by PGE(2): (i) cAMP cross-talk with MAPK pathways is limited in gingival fibroblasts; (ii) PGE(2) activation of the EP3 prostanoid receptor stimulates the activation of JNK.

TGF beta1 expression and angiogenesis in colorectal cancer tissue.

Transforming growth factor TGF beta1 is involved in a variety of important cellular functions,including cell growth and differentiation, angiogenesis, immune function and extracellular matrix formation. However, the role of TGF beta(1) as an angiogenic factor in colorectal cancer is still unclear. We investigate the relationship between transforming growth factor beta(1) and angiogenesis by analyzing the expression of transforming growth factor TGF beta(1) in colorectal cancer, as well as its association with VEGF and MVD. The expression of TGF beta(1),VEGF, as well as MVD were detected in 98 colorectal cancer by immunohistochemical staining. The relationship between the TGF beta(1) expression and VEGF expression,MVD was evaluated. To evaluate the effect of TGF beta(1) on the angiogenesis of colorectal cancers. Among 98 cases of colorectal cancer,37 were positive for TGF beta(1) 37.8% 36 for VEGF 36.7% respectively. The microvessel counts ranged from 19 to 139.8, with a mean of 48.7(standard deviation,21.8). The expression of TGF beta(1) was correlated significantly with the depth of invasion, stage of disease, lymph node metastasis, VEGF expression and MVD. Patients in T3-T4, stage III-IV and with lymph node metastasis had much higher expression of TGF beta(1) than patients in T1-T2, stage I-II and without lymph node metastasis (P<0.05). The positive expression rate of VEGF(58.3%) in the TGF-beta(1) positive group is higher than that in the TGF-beta(1) negative group(41.7%, P<0.05). Also, the microvessel count (54+/-18) in TGF-beta(1) positive group is significantly higher than that in TGF-beta(1) negative group(46+/-15, P<0.05). The microvessel count in tumors with both TGF-beta(1) and VEGF positive were the highest (58+/-20 36-140, P<0.05). Whereas that in tumors with both TGF-beta(1) and VEGF negative were the lowest (38+/-16, 19-60, P<0.05). TGF beta(1) might be associated with tumor progression by modulating the angiogenesis in colorectal cancer and TGF beta(1) may be used as a possible biomarker.

Long-term expression of transforming growth factor TGF beta1 in mouse skin after localized beta-irradiation

The long-term expression of TGF beta 1 in mouse skin after localized irradiation with a beta-emitting source is reported. The skin of CBA/ca mice was exposed to 50 Gy superficial beta radiation from an 11 mm strontium-90 source. Such a dose produced an acute moist desquamation reaction in 100% of the animals, which was macroscopically resolved within 30 days. The acute response was followed by progressive remodelling of dermal tissues as characterized by histological means. The expression of TGF beta 1 was followed for 12 months after irradiation and showed three distinct waves of expression at the RNA level. Levels of expression initially rose to 230% above controls at 6 h before returning to control levels around 24-48 h. Expression then rose again to 169 and 234% above controls at 14 and 28 days post-irradiation respectively. Levels then declined to those of the controls by 2 months. A progressive increase in expression was then noted after 3 months, which peaked around 9 months and was resolved by 12 months. In a parallel study the skin of 144 CBA/ca mice was exposed to 50 Gy superficial beta radiation from 2 x 4 cm Thulium-170 source and compared with a similar group of sham-irradiated controls. The irradiated group showed a cumulative tumour incidence of 54.3% compared with 0% incidence in the sham-irradiated group. Of the 45 radiation-induced tumours a representative sample of 16 (nine malignant fibrous histiocytomas; three fibrosarcomas; two fibromas; one squamous cell carcinoma; one rhabdomyosarcoma) were selected for further study. Semiquantitative PCR on all these tumours showed elevated levels of TGF beta 1 expression ranging from 1.8 to 87-fold above the levels found in normal skin. This study is part of ongoing investigations into the long-term effects of single accidental exposures. The 50 Gy dose used is comparable with the surface doses obtained by some of the victims of the Chernobyl accident.